1. Field of the Invention
This invention is directed to compounds that provide for sustained systemic concentrations of GABA analogs following administration to animals. This invention is also directed to pharmaceutical compositions and methods of use that employ such compounds.
2. State of the Art
Rapid clearance of drugs from the systemic circulation represents a major impediment to effective clinical use of therapeutic and/or prophylactic compounds. Although multiple factors can influence the systemic concentrations of drugs achieved following administration (including drug solubility, dissolution rate, first-pass metabolism, p-glycoprotein and related efflux mechanisms, hepatic/renal elimination, etc), rapid systemic clearance is a particularly significant reason for suboptimal systemic exposure to many compounds. Rapid systemic clearance may require that large doses of drug be administered to achieve a therapeutic or prophylactic effect. Such larger doses of the drug, however, may result in greater variability in drug exposure, more frequent occurrence of side effects, or decrease in patient compliance. Frequent drug administration may also be required to maintain systemic drug levels above a minimum effective concentration. This problem is particularly significant for drugs that must be maintained in a well-defined concentration window to provide continuous therapeutic or prophylactic benefit while minimizing adverse effects (including for example, antibacterial agents, antiviral agents, anticancer agents, anticonvulsants, anticoagulants, etc.).
Conventional approaches to extend the systemic exposure of drugs with rapid clearance involve the use of formulation or device approaches that provide a slow or sustained release of drug within the intestinal lumen. These approaches are well known in the art and normally require that the drug be well absorbed from the large intestine, where such formulations are most likely to reside while releasing the drug. Drugs that are amenable to conventional sustained release approaches must be orally absorbed in the intestine and traverse this epithelial barrier by passive diffusion across the apical and basolateral membranes of the intestinal epithelial cells. The physicochemical features of a molecule that favor its passive uptake from the intestinal lumen into the systemic circulation include low molecular weight (e.g. <500 Da), adequate solubility, and a balance of hydrophobic and hydrophilic character (log P generally 1.5-4.0) (Navia and Chaturvedi, P. R. Drug Discovery Today 1996, 1, 179-189).
Polar or hydrophilic compounds are typically poorly absorbed through an animal's intestine, as there is a substantial energetic penalty for passage of such compounds across the lipid bilayers that constitute cellular membranes. Many nutrients that result from the digestion of ingested foodstuffs in animals, such as amino acids, di- and tripeptides, monosaccharides, nucleosides and water-soluble vitamins, are polar compounds whose uptake is essential to the viability of the animal. For these substances there exist specific mechanisms for active transport of the solute molecules across the apical membrane of the intestinal epithelia. This transport is frequently energized by co-transport of ions down a concentration gradient. Solute transporter proteins are generally single sub-unit, multi-transmembrane spanning polypeptides, and upon binding of their substrates are believed to undergo conformational changes, which result in movement of the substrate(s) across the membrane.
Over the past 10-15 years, it has been found that a number of orally administered drugs are recognized as substrates by some of these transporter proteins, and that this active transport may largely account for the oral absorption of these molecules (Tsuji and Tamai, Pharm. Res. 1996, 13, 963-977). While in most instances the transporter substrate properties of these drugs were unanticipated discoveries made through retrospective analysis, it has been appreciated that, in principle, one might achieve good intestinal permeability for a drug by designing in recognition and uptake by a nutrient transport system. Drugs subject to active absorption in the small intestine are often unable to passively diffuse across epithelial cell membranes and are too large to pass through the tight junctions that exist between the intestinal cells. These drugs include many compounds structurally related to amino acids, dipeptides, sugars, nucleosides, etc. (for example, many cephalosporins, ACE inhibitors, AZT, gabapentin, pregabalin, baclofen, etc.)
One pathway that might provide for the sustained delivery of drugs with rapid systemic clearance is the proton-coupled peptide transporters (Leibach and Ganapathy, Ann. Rev. Nutr. 1996, 16, 99-119). Such transporters mediate the cellular uptake of small intact peptides consisting of two or three amino acids and are found primarily in the intestine and kidney. In the intestine, where small peptides are not well-absorbed through passive diffusion, the transporters act as a vehicle for their effective absorption. Transporters in the kidney actively reabsorb di- and tri-peptides from the glomerular filtrate, thereby increasing their half-life in the circulation.
Two proton-coupled peptide transporters that have been cloned and characterized are PEPT1 and PEPT2. PEPT1 is a low-affinity, high-capacity transporter found primarily in the intestine. The human PEPT1 consists of 708 amino acids and possesses 12 putative transmembrane domains. PEPT2, in contrast, is a high-affinity, low-capacity transporter found mostly in the kidney. It consists of 729 amino acids and is 50% identical to human intestinal PEPT1.
Studies of PEPT1 and PEPT2 have shown that the transporters account for the absorption and reabsorption of certain therapeutically active compounds. The compounds include both biologically active peptides (e.g., renin inhibitors) and zwitterionic antibiotics. Based on these observations, researchers have suggested that peptide transporters, in conjunction with cytosolic peptidases, could be exploited for systemic delivery of certain drugs in the form of peptide prodrugs. Dipeptide analogues of α-methyldopa, L-α-methyldopa-Phe and L-α-methyldopa-Pro, for example, are absorbed more efficiently in the intestine than α-methyldopa alone. Once across the intestinal membrane, the dipeptides are hydrolyzed by cytosolic peptidases to release α-methyldopa.
While the general suggestion of exploiting proton-coupled peptide transporters to enhance the absorption of poorly absorbed drugs has been made, the existing art does not teach a method that can be used successfully to design and construct a peptide prodrug of any given drug. Moreover, while the existing art discusses improving intestinal absorption of poorly absorbed drugs, it does not teach methods for achieving sustained systemic concentrations of drugs following administration to animals.